Synergistic effects of gefitinib used in combination with S-1 have been reported because of a reduction in the expression of thymidilate synthase in use of gefitinib. Erlotinib also reduced TS expression and activity. The present studies were designed to evaluate the efficacy and safety of erlotinib/S-1 combination therapy as a second/third-line therapy for recurrent/advanced NSCLC.Methods
Chemotherapy consisted of two 3-week cycles of erlotinib and S-1 treatment. Erlotinib was orally administered once daily at a dose of 150 mg/body, and patients received an oral dose of S-1 twice daily from days 1 to 14 of each 21-day cycle. In phase I trial (TORG0808), the primary end points were to evaluate the DLT and MTD for the following phase II study, and the secondary end points were the antitumor activity and safety. Based on the phase I trial, we conducted a phase II trial (TORG0913) of this combination with pretreated EGFR negative NSCLC to determine the ORR. The secondary end points were PFS, disease control rate, OS and safety.Results
Seven patients with good PS (0 or 1) and 10 patients with PS 0-2 participated in phase I and II trials, respectively. In phase I trial, the recommended doses for the phase II study were determined to be 150 mg/body for erlotinib and 80 mg/m2 for S-1. The ORR was 67%, and three of four responders were EGFR-positive patients. In phase II trial, the ORR was very low (only one patient). Myelosuppression was relatively mild, but grade 3 or worse non-hematological toxicities including diarrhea, mucositis and dermatitis were observed in six patients, which resulted in two treatment-related deaths. Data and Safety Monitoring Committee recommended the early termination.Conclusions
Phase I study showed the favorable efficacy and moderate safety profiles of this combination especially in EGFR-positive patients, but phase II trial demonstrated less effective and too toxic results in EGFR negative patients.